tbuckley/cabot-search huggingface dataset:
Genomic aberrations associated with overall survival (OS) in metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) or placebo (PBO) plus androgen deprivation therapy (ADT) in TITAN.
Authors: Neeraj Agarwal, Justin Lucas, Clemente Aguilar-Bonavides, Shibu Thomas, Michael Gormley, Simon Chowdhury, Axel S. Merseburger, Anders Bjartell, Hirotsugu Uemura, Mustafa Özgüroğlu, Sharon McCarthy, Sabine D. Brookman-May, Florence Lefresne, Suneel Mundle, Kim N. Chi
Journal: Journal of Clinical Oncology (2022)

5066 Background: TITAN, a phase 3 PBO-controlled study in patients (pts) with mCSPC, showed APA + ADT improved radiographic progression-free survival and OS vs PBO + ADT. In this exploratory analysis, we report the relationships between biomarkers and OS in TITAN. Methods: Circulating tumor (ct)DNA and genomic aberrations in 17 PC-related genes, including androgen receptor (AR), were assessed at baseline (BL; 114 pts) and end of study treatment (EOST; 129 pts) using next-generation sequencing. ctDNA was assessed qualitatively; genomic aberrations were assessed within ctDNA-positive samples as inactivation (heterozygous/homozygous deletion or single nucleotide variant [SNV]) or activation (amplification or SNV). Associations of detected ctDNA/aberrations at BL or EOST with OS, and biomarkers at EOST with OS on subsequent therapies, were evaluated using univariate or multivariate analyses and Cox proportional hazards model; results were stratified by treatment arm. Results: Among pts from both treatment groups, 36% had detectable ctDNA, of which 27% had any genomic AR aberration and 24% had AR gene amplification at BL; prevalence of these biomarkers increased significantly from BL to EOST (Table). The most prevalent non-AR aberrations at BL ( TP53, homologous recombination repair [HRR] pathway, PTEN, RB1, and PIK3CA genes) increased at EOST but not significantly (Table). Among assessed aberrations, presence of ctDNA or any AR genomic aberrations at BL (HR, 1.9 or 6.7; all p &lt; 0.05) and any AR genomic aberrations or PI3K pathway activation at EOST (1.7, p &lt; 0.05 or 2.2, p &lt; 0.001) was significantly associated with poor OS in multivariate analyses from both treatment groups. In univariate analyses of pts who received subsequent therapy (chemotherapy: 106; hormonal therapy: 161), worse OS was associated only with PIK3CA activation, PI3K pathway activation, or TP53 inactivation at EOST (3.7, p &lt; 0.05; 2.4, p &lt; 0.05; 3.0, p &lt; 0.01, respectively) in chemo-treated pts. A small sample size in some biomarker subgroups limits interpretation. Conclusions: These hypothesis-generating data from TITAN show that presence of ctDNA or select AR and non-AR biomarkers at BL or EOST were associated with poor OS. The predictive value of these biomarkers for survival in mCSPC needs further confirmation. Clinical trial information: NCT02489318. [Table: see text]
Whole genome sequencing of HER2+ metastatic breast cancer and CNA comparison between long term survivor and short-term survivor.
Authors: Charlotte Andrieu, Caoimhe Goldrick, Darko Skrobo, Alex Eustace, Jo Ballot, Cecily Quinn, Giuseppe Gullo, Naomi Walsh, John Crown
Journal: Journal of Clinical Oncology (2022)

e13019 Background: The introduction of anti-HER2 therapies such as trastuzumab for HER2+ metastatic breast cancer (MBC) has led to significant improvements to disease progression. We and others have reported long-term durable complete response to trastuzumab in patients with HER2+ MBC. We hypothesise that genomic copy number alteration (CNA) and tumour mutational burden (TMB) may act as a prognostic measure of predicting response to trastuzumab in long-term survivors (LTS) compared to short-term survivors (STS). Using whole-genome sequencing (WGS) to detect these alterations, we aim to identify the molecular characteristics of primary and metastatic lesions in patients with metastatic HER2+ breast cancer. Methods: WGS was performed on samples from two patients from a HER2+ MBC cohort; a of long-term survivor (PFS 27 months; OS &gt; 60 months) and a short-term survivor (PFS 4 months; OS &lt; 14 months). Primary tumours, adjacent normal tissue and metastases were sequenced at a mean depth of 60X. Reads were aligned on the hg38 reference genome using Burrows-Wheeler Aligner (bwa), CNA were detected using Control-FREEC to evaluate total CNA burden. Single nucleotide variants were detected using GATK Mutect2 to calculate TMB. Results: Analysis of DNA chromosome disruption (fraction of the genome amplified/deleted) revealed a higher overall fraction of disrupted genome in the LTS primary tumour and metastasis compared with the STS (0.061 and 0.064 vs 0.031 and 0.047, respectively). Further delineation of the distribution of CNA burden in all genomes identified chr1 as the most altered in the STS samples whereas chr17 was the most disrupted in the LTS samples. HER2 and CDK12 were amplified in both LTS and STS samples (4 copies in LTS primary tumour and metastasis, 18 and 14 copies in STS primary tumour and metastasis respectively). A high TMB was estimated in both samples but was higher in the STS primary tumour than in the LTS one (161 vs 142, respectively). TMB was increased in LTS metastatic lesions. NRAS mutation was found in LTS primary tumour but was lost in the metastasis. Conclusions: This pilot study highlights the potential for whole-genome sequencing to identify CNA and TMB in HER2+ MBC in patients who display long-term and short-term survival. Further samples from this cohort need to be studied to investigate the relationship between CNA burden and HER2+ MBC patient survival.
Trends of leukemia mortality in the United States, 1999-2018.
Authors: Bibek Bakhati, Karthik Chamarti, Victoria Sibi, Thao Dang, Kelash Bajaj
Journal: Journal of Clinical Oncology (2022)

e19034 Background: Malignant neoplasms are the second leading cause of mortality in the United States. Among the cancer sites, leukemia is the seventh most common cause of deaths. It accounts for 3.2% of all new cases of cancer and 3.9% of all cancer deaths. The Mortality-to-Incidence Ratio (MIR) has previously been applied as a measure to examine health disparities and outcomes of cancer therapy. In this study, we aim to analyze leukemia incidence, mortality, and trends of MIR for gender and race over the previous two decades. Methods: We conducted a retrospective population-based study using Cancer Statistics from the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research system (CDC WONDER). Subjects with leukemia as the cancer site were selected. Age-adjusted mortality and age-adjusted incidence rates for race and gender were obtained and reported over 100,000 people. Negative binomial regression analysis using age-adjusted rates was subsequently used to analyze mortality, incidence, and trends of MIR. Results: 448,893 deaths were reported to be associated with leukemia between 1999 and 2018, of which males accounted for 56.85%. A total of 894,726 incident cases of leukemia were recorded during the same period. Males had a higher age-adjusted mortality rate than females (9.3 vs 5.2, OR: 1.70 [1.48-1.95]). Compared to Native Americans, African Americans and White cohorts had substantially higher age-adjusted mortality rates (3.5, 6.0, 7.2, OR: reference, 1.74, 2.05), whereas Asians had a non-significantly higher rate (3.8, OR: 1.09 [0.87-1.36]). In males, incidence rates were significantly higher (17.9, OR: 1.61 [1.58-1.64]). Against White population, Asian and African American race had a significantly lower age-adjusted incidence rate (14.4, 7.9, 10.6, OR: reference, 0.60, 0.79), while Native American race had a significantly higher rate (8.2, OR: 1.15 [1.06-1.24]. The mortality-to-incidence ratio has decreased significantly over time in both male and female populations (22.82% and 27.62%, respectively), as well as in African American and White cohorts (24.36% and 23.24%, respectively). Conclusions: Over the last 20 years, the mortality-to-incidence rate ratio significantly declined, possibly suggesting the effectiveness of cancer treatment outcomes in the United States. Yet, the reduction in mortality was not observed in all races. More efforts and further research are needed to guide the policy change.
Final result for SAFIA trial for neoadjuvant palbociclib in patients with operable luminal breast cancer responding to fulvestrant.
Authors: Khalid A. Al-Saleh, Heba Mohamed El Zawahry, Adda Bounedjar, Mohammed Oukkal, Ahmed Saadeddin, Hassen Mahfouf, Bouzid Kamel, Assia Bensalem, Hikmat Abdel-Razeq, Alaa Kandil, Omalkhair A. M. Abulkhair, Meteb Owaish Al-Foheidi, Marwan Ghosn, Hamouda Boussen, Abderrazak Haddaoui, Jihene Braham Ayari, Mohammed Alghamdi, Nashwa A. Abdulaziz, Sharif Ahmed Kullab, Jean-Marc A. Nabholtz
Journal: Journal of Clinical Oncology (2022)

596 Background: Luminal, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) encompasses the most common subtype of breast malignancies. Neoadjuvant strategies of operable BC are primarily based upon chemotherapy (CT), while neoadjuvant hormone therapy (NAHT) has not been well studied in the Middle East and North Africa (MENA) region. However, these tumors might respond poorly to neoadjuvant CT with significant side effects, emphasizing the need to identify patients who could be candidates for NAHT. Methods: The SAFIA trial is a prospective multicentre, international, double-blind, neoadjuvant phase-III trial using upfront 21-gene Oncotype DX Breast Recurrence Score assay (RS) &lt;31) to select operable Luminal HER2-negative patients for induction hormonal therapy with Fulvestrant 500 mg +/– Goserelin (F/G) before randomizing responding patients to F/G + Palbociclib (Cyclin-Dependent Kinase 4/6 inhibitor / CDK 4/6) versus F/G + Placebo. The primary endpoint of this study was the complete pathologic response (pCR) rate. Results: A total of 354 patients were enrolled, leading to 277 patients treated with induction F/G. Of these, 253 responding patients were randomized to F/G fulvestrant with palbociclib or Placebo. Two hundred and thirty patients were evaluable for pathologic response. No statistically significant differences were identified in terms of pCR rates between F/G with palbociclib or placebo: 2% versus 7%, respectively. According to the radiologic responses post- induction F/G, the hormone sensitivity rate was 89.8%, while the clinical benefit of 8–9 months of neoadjuvant F/G was 96%. Safety in the MENA population was acceptable with a grade 3-4 neutropenia rate of 25% in the F/G plus palbociclib arm. The feasibility of performing the 21-gene breast recurrence score assay on core biopsy specimens was optimal in 96.4% of cases. Conclusions: The addition of palbociclib to neoadjuvant F/G did not show any additional benefit in terms of pathologic response, including pCR in neoadjuvant therapy of Luminal HER2-negative BC responding to induction F/G. The use of an upfront 21-gene assay appeared feasible on biopsy specimens, and the identification of tumors with RS&lt;31 allowed to select endocrine sensitive patients, leading ultimately to a 96% clinical benefit with 8–9 months of F/G neoadjuvant therapy. Clinical trial information: NCT03447132. [Table: see text]
The outcome and prognostic factors of advanced non-small cell lung cancer patients with do-not-intubation order in intensive care unit.
Authors: Chia-I Shen, Shan-Yao Yang, Hwa-Yen Chiu, Wei-Chih Chen, Wen-Kuang Yu, Kuang-Yao Yang
Journal: Journal of Clinical Oncology (2022)

e24113 Background: The survival of lung cancer patients in critical care has been improved. Increasing number of lung cancer patients have signed predefined do-not-intubation (DNI) order before admission to ICU. These patients may still be transferred to ICU and even receive non-invasive ventilation (NIV) supports. However, there is still lack of prognostic prediction in this cohort. Whether patients will be benefit of ICU care remain unclear. Methods: We retrospectively collected data of patients with advanced lung cancer, having signed DNI order before ICU admission in a tertiary medical center. The clinical characteristics and survival outcomes were discussed. The enrollment duration is between 2014 to 2016. Results: Total 140 patients were included. All patients were diagnosed with stage III or IV non-small cell lung cancer (AJCC 7 th edition) and signed DNI. The median age was 73 years old and about two-thirds were male. Most patients had received NIV during ICU course. The median APACHE II score was 14 (SE, 0.66) and the mean P/F ratio was 174.2(+/-104) mmHg. The APACHE II score was significantly lower in 28-day survivors (survivor 12 (+/-0.98) vs non-survivor 15 (+/-0.83), p = 0.019). The P/F ratio of the survivors was higher than non-survivors (survivor 209.6+/-111.4 vs non-survivor 157.9+/-96.7, p = 0.006). Patients with P/F ratio ≥150 had better 28-day survival (p = 0.005). By combining P/F ratio≥150 and APACHE II score &lt; 16, those with high P/F ratio and low APACHE II score during ICU admission had a notable 28-day survival compared with the rest (p &lt; 0.001). These prognostic factors could also be applied for 90-day survival (p = 0.003). The prediction model was significant in those with driver mutations in 90-day survival (p = 0.021) but not in those without driver mutations (p = 0.061). Conclusions: The P/F ratio≥150 and APACHE II score &lt; 16 were the prognostic significance of critically ill lung cancer patients with DNI. The prediction could be applied for 90-day survival in patients with driver mutation. The finding was informative for clinical practice and decision-making.
Molecular stratification of response and survival of venetoclax in combination with hypomethylating agents in AML.
Authors: Keri Renee Maher, Ian Michael Bouligny
Journal: Journal of Clinical Oncology (2022)

e19033 Background: The use of venetoclax, a BCL-2 antagonist, in combination with decitabine or azacitidine has become routine for the upfront treatment of patients with acute myeloid leukemia (AML) not eligible for intensive induction. The impact of the addition of venetoclax to hypomethylating agents (HMAs) on outcomes with respect to various gene mutations is currently unclear. The aim of this study was to investigate response and survival of patients with AML receiving venetoclax-based induction with respect to specific molecular aberrations. Methods: We retrospectively analyzed 41 patients with AML treated with upfront venetoclax + HMAs from July 2017 to December 2020 at VCU Massey Cancer Center. Baseline patient demographics were obtained, including molecular profiling either through PCR or NGS at the time of induction, alongside cytogenetic risk, doses of induction regimens, response including MRD analysis, and survival. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. Results: Nine patients were identified with NPM1 mut and 66.6% were ELN adverse risk. The composite response rate (CRR = CR + CRi) was 44.4% and the OS was 8.2 months. Seven patients had either DNMT3A mut or DNMT3B mut and 57.1% were classified as adverse risk. The CRR was 28.6% and the mOS was not reached after a median follow-up time of 15.1 months. Eleven patients had FLT3-ITD mut or FLT3-TKD mut and 81.8% were classified as adverse risk. The CRR was 45.6% and the OS was 6.3 months. Six patients had either NRAS mut or KRAS mut . The CRR was 16.7% and the OS was 8.9 months. Seven patients had ASXL1 mut , the CRR was 28.5% with the OS not reached at a median follow-up time of 8.9 months. Six patients with RUNX1 mut demonstrated a CRR of 50.0% and the OS was not reached at a follow-up time of 12.8 months. Nine patients had TP53 mut with a CRR of 33.3% and OS 12.6 months. Conclusions: Survival with venetoclax + HMA appears to numerically favor TP53 mut AML when compared to more intensive strategies, consistent with prior literature reporting favorable responses to HMA monotherapy in this subset of disease. FLT3 mut appeared to have a relatively lower OS, though not significantly different from either NPM1 mut or TP53 mut at the time of this analysis. DNMT3 mut AML may preferentially respond to venetoclax + HMAs given the 15.1 month duration of follow-up, though longer follow-up with larger cohorts are needed to further identify subsets of molecularly stratified preferential responders to venetoclax-based strategies.[Table: see text]
Laterality and survival in mesothelioma: A SEER database analysis.
Authors: Jay Parekh, Aslihan Yerlikaya, Yiyu Xie, Yesim Eralp, Yaw Adjepong
Journal: Journal of Clinical Oncology (2022)

e20594 Background: Malignant pleural mesothelioma (MPM) is a highly aggressive and rare cancer type that carries dismal prognosis with a median survival of only 12 months. Often patients are diagnosed at advanced age and tend to have many co-morbid conditions. More precise prognostication should help physicians to decide on the best treatment approach for patients. Previous three studies suggest right sided involvement is associated with poorer prognosis. However, these were very small studies and estimates were not precise. We therefore decided to assess prognostic indicators, including laterality, using the large SEER database. Methods: Using SEER database, a total of 5064 cases diagnosed between 1975-2003 were included in this study. R software (4.0.5) was used. Prognostic indicators assessed included age, stage at diagnosis (distant versus regional/early), gender, and tumor laterality. We evaluated all-cause mortality using multivariate regression and introduced a competing risk regression to explore the association of clinical features and mesothelioma-related death. In analyses, we treated non-cancer related death as a competing factor. The prognostic significance of laterality was assessed at each stage of diagnosis. Results: The patients were predominantly male (81%), aged 60 years or older (79.1%) with right side predominance (58.9%). The overall median survival time was 8 months. The cumulative incidence of mesothelioma-specific death was 42% at 6 months and 62% at 12 months. In the multivariate analysis, male gender (HR = 1.23, p &lt; 0.01), age 60 year or older (HR = 1.52, p &lt; 0.01) and distant stage at diagnosis (HR = 1.2, p &lt; 0.01) were independent predictors of shorter overall survival. In subgroup analyses of different stages, right sided mesothelioma was an independent predictor of mesothelioma-related death(HR = 1.14, CI 1.00-1.28, p = 0.042) in patients with regional/early-stage disease (Table) after adjustment for age and gender. When included all cohort with both early and late stages, there was no statistically significant association between laterality and all-cause mortality(HR = 1.02, CI 0.958-1.08, p = 0.61). Conclusions: Our study confirms that right-sided involvement is independently associated with increased risk of death in early stage/localized mesothelioma patients. The lack of association between laterality and survival in those with distant spread may be explained by the overall shorter survival in that group.[Table: see text]
Racial differences in genomic profiling of prostate cancer at the durham veterans affairs medical center.
Authors: Matthew Labriola, Rhonda L. Bitting
Journal: Journal of Clinical Oncology (2022)

e17002 Background: Black men are underrepresented in precision oncology studies. Mahal et al. found that black men with metastatic PCa who had genomic profiling (GP) more commonly had mutations in DNA damage repair (DDR) and actionable genes, although only 8.5% of men in the study were black. [i] Here, we examine racial differences in GP in men with PCa at the Durham Veterans Affairs Medical Center (DVAMC). Methods: Men with PCa who had GP completed by Foundation Medicine at DVAMC from 2/2019-2/2022 were included. Reports were analyzed for mutations of interest. Biopsy site and patient demographics were extracted on chart review. Results: 155 men had GP at the DVAMC during the study period. Importantly 88 (57%) men were black and 67 (43%) were white. Sequencing was performed on the primary tumor (n = 80, 52%), metastatic site (n = 25, 16%), or circulating tumor (ct) DNA (n = 50, 32%). GP was performed on both tissue and ctDNA in 8% of patients, 58% had concordant findings. Racial differences in actionable mutations, DDR mutations, and mutations approved for PARP inhibitor use are noted in Table. The most commonly altered gene is TP53 (n = 59), more prevalent in black men (n = 36, 61%). ATM mutations are more common in black men, 10/14 (71%), however 85% of these are identified on ctDNA and n = 5 had an allele fraction of &lt; 1% suggestive of clonal hematopoiesis of indeterminate potential (CHIP). In contrast, 8/9 (89%) of PIK3CA mutations and 25/36 (69%) of TMPRSS fusions were found in white men. Conclusions: Black men comprised a majority of the patients with PCa who had GP at the DVAMC. We found no statistically significant differences between black and white men in incidence of actionable mutations, DDR mutations, or mutations approved for PARP inhibitor use. PIK3CA alterations and TMPRSS fusions are enriched in white men, consistent with published literature, however, ATM and TP53 mutations are enriched in black men, discordant with findings from Mahal et al, raising the possibility that GP in veterans differs due to environmental exposures. ATM mutations are predominantly found in ctDNA, which may represent CHIP. Expansion of the above analysis could offer insight into racial differences in tumor biology.[Table: see text]